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Dr. Amir Khan

Associate Professor (Biochemistry)
      
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Dr. Amir Khan

Associate Professor (Biochemistry)

 Amir.Khan@tcd.ie

 3531896 3868


  CONGENITAL HEMANGIOPERICYTOMA   EXTERNAL CAROTID ARTERY LIGATION   LIFE-THREATENING HEMORRHAGE
Project Title
 LRRK2 Control of Membrane Trafficking in Health and Disease
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Summary
The most common cause of inherited Parkinson"s disease is a mutation in Leucine-Rich Repeat Kinase 2 (LRRK2). LRRK2 is implicated in numerous cellular processes including autophagy, mitochondrial dynamics, and ciliogenesis. Despite its importance there is little structural information on LRRK2 signaling pathways. In 2016, Rab GTPases were identified as the first bona fide substrates of LRRK2. Rabs are molecular switches that localize to subcellular compartments and regulate membrane trafficking through recruitment of cytosolic effector proteins. LRRK2 is an effector of Rab29 and is recruited to Golgi where it phosphorylates Rab8a and Rab10. Here we will investigate the molecular basis for the LRRK2 and Rab signaling cascade using X-ray crystallography. The structural basis for Rab29 binding to LRRK2 will be determined. Downstream pathways involving the interactions between phosphorylated Rab8a/10 and phospho-specific effector proteins will be studied using structural and biophysical techniques. Finally, we will investigate the structure and function of PPM1H phosphatase which counters LRRK2 activation by dephosphorylating Rab GTPases. Reversible phosphorylation of Rab GTPases has emerged as a critical regulatory mechanism that is associated with LRRK2 signaling cascades. The project will address fundamental questions on the physiological role of LRRK2 through its regulatory and substrate Rab GTPases.
Funding Agency
Science Foundation Ireland
Programme
Research Frontiers
Person Months
48

Fram B, Su Y, Truebridge I, Riesselman A.J, Ingraham J.B, Passera A, Napier E, Thadani N.N, Lim S, Roberts K, Kaur G, Stiffler M.A, Marks D.S, Bahl C.D, Khan A.R, Sander C, Gauthier N.P, Simultaneous enhancement of multiple functional properties using evolution-informed protein design, Nature Communications, 15, (1), 2024, Journal Article, PUBLISHED  DOI  URL
Benarroch Y, Juttukonda L, Sabharwal V, Boateng J, Khan A.R, Yarrington C, Wachman E.M, Taglauer E, Differential Expression of Rab5 and Rab7 Small GTPase Proteins in Placental Tissues From Pregnancies Affected by Maternal Coronavirus Disease 2019, Clinical Therapeutics, 43, (2), 2021, p308 - 318, Journal Article, PUBLISHED  DOI  URL
Dieter Waschbuesch, Kerryn Berndsen, Pawel Lis, Axel Knebel, Yuko PY Lam, Dario R Alessi & Amir R Khan, Structural basis for the specificity of PPM1H phosphatase for Rab GTPases, EMBO reports, 22: e52675, 2021, p10.15252/embr.202152675 , Journal Article, PUBLISHED  DOI  URL
Dieter Waschbuesch, Elena Purlyte, Amir R Khan, Dual arginine recognition of LRRK2 phosphorylated Rab GTPases, Biophysical Journal, 120, (9), 2021, p1846 - 1855, Journal Article, PUBLISHED  DOI  URL
Strofaldi A, Khan A.R, McManus J.J, Surface Exposed Free Cysteine Suppresses Crystallization of Human γD-Crystallin, Journal of Molecular Biology, 433, (22), 2021, Journal Article, PUBLISHED  DOI  URL
Kearney A.M, Khan A.R, Crystal structure of the Rab-binding domain of Rab11 family-interacting protein 2, Acta Crystallographica Section F: Structural Biology Communications, 76, 2020, p357 - 363, Journal Article, PUBLISHED  DOI  URL
Dieter Waschb€usch, Elena Purlyte, Prosenjit Pal, Emma McGrath, Dario R. Alessi, Amir R. Khan, Structural Basis for Rab8a Recruitment of RILPL2 via LRRK2 Phosphorylation of Switch 2, Structure, 28, (1-12), 2020, p10.1016/j.str.2020.01.005 , Notes: [PMID: 32017888 ], Journal Article, PUBLISHED  DOI  URL  URL
Dieter Waschbuesch and Amir R Khan, Phosphorylation of Rab GTPases in the regulation of membrane trafficking, Traffic, 21, (11), 2020, p712 - 719, Review Article, PUBLISHED  DOI  URL
Garg, R.R. and Jackson, C.B. and Rahman, M.M. and Khan, A.R. and Lewin, A.S. and McFadden, G., Myxoma virus M013 protein antagonizes NF-κB and inflammasome pathways via distinct structural motifs, Journal of Biological Chemistry, 294, (21), 2019, p8480-8489 , Notes: [cited By 0], Journal Article, PUBLISHED  DOI
WaschbÃŒsch, D. and HÃŒbel, N. and Ossendorf, E. and Lobbestael, E. and Baekelandt, V. and Lindsay, A.J. and McCaffrey, M.W. and Khan, A.R. and Barnekow, A., Rab32 interacts with SNX6 and affects retromer-dependent Golgi trafficking, PLoS ONE, 14, (1), 2019, Notes: [cited By 0], Journal Article, PUBLISHED  TARA - Full Text  DOI
  

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Award Date
Cyril M. Kay Book Prize in Biochemistry University of Alberta 1995
Studentship, Medical Research Council of Canada 1996
Student Travel Award, American Crystallographic Association St. Louis, MI 1997
Finn Wold Travel Award, Eleventh Symposium of the Protein Society, Boston, MA 1997
Dissertation Fellowship, University of Alberta 1998
Graduate Student Poster Prize, CFBS Annual Meeting Edmonton, Alberta 1998
Fellowship, Human Frontiers Science Program 1999
Fellowship, Centre National de la Recherche Scientifique (CNRS), France 2001
Fellowship, Canadian Institutes of Health Research (CIHR) 2002
Research Grant, Scientific Investigator Programme, Science Foundation Ireland 2004
Our lab is interested in the molecular mechanisms that underpin human health and disease. We exploit numerous biochemical, biophysical and structural techniques to enable a visualization of the 3-D structure of proteins signaling complexes. With the advent of 3-D prediction algorithms such as AlphaFold, our toolbox for understanding cellular processes at the molecular level has greatly expanded. We have a particular interest in the molecular basis for inherited forms of Parkinson"s disease. The autosomal dominant gene LRRK2 codes for a protein called LRRK2 kinase, which acquires enhanced activity and leads to neuronal cell death. LRRK2 phosphorylates its substrates, Rab GTPases, and dramatically alters cellular homeostasis. We are trying to understand this signaling pathway with a view to identifying new routes for therapeutics to treat the disease.